8-22130605-T-C

Position:

• chr8-22130605-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_005144.5(HR):​c.-218A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: HR NM_005144.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.46

Genes affected

HR (HGNC:5172): (HR lysine demethylase and nuclear receptor corepressor) This gene encodes a protein that is involved in hair growth. This protein functions as a transcriptional corepressor of multiple nuclear receptors, including thyroid hormone receptor, the retinoic acid receptor-related orphan receptors and the vitamin D receptors, and it interacts with histone deacetylases. The translation of this protein is modulated by a regulatory open reading frame (ORF) that exists upstream of the primary ORF. Mutations in this upstream ORF cause Marie Unna hereditary hypotrichosis (MUHH), an autosomal dominant form of genetic hair loss. Mutations in this gene also cause autosomal recessive congenital alopecia and atrichia with papular lesions, other diseases resulting in hair loss. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2014]

HRURF (HGNC:55085): (HR upstream open reading frame) Implicated in hypotrichosis 4. [provided by Alliance of Genome Resources, Apr 2022]

HR (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-22130605-T-C is Pathogenic according to our data. Variant chr8-22130605-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 7344.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HR	NM_005144.5	c.-218A>G		5_prime_UTR_premature_start_codon_gain_variant	1/19	ENST00000381418.9	NP_005135.2
HRURF	NM_001394132.1	c.104A>G	p.Ter35Trpext*?	stop_lost	1/1	ENST00000518377.3	NP_001381061.1
HR	NM_005144.5	c.-218A>G		5_prime_UTR_variant	1/19	ENST00000381418.9	NP_005135.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HR	ENST00000381418.9	c.-218A>G		5_prime_UTR_premature_start_codon_gain_variant	1/19	1	NM_005144.5	ENSP00000370826.4
HRURF	ENST00000518377.3	c.104A>G	p.Ter35Trpext*?	stop_lost	1/1	4	NM_001394132.1	ENSP00000505144.1
HR	ENST00000381418.9	c.-218A>G		5_prime_UTR_variant	1/19	1	NM_005144.5	ENSP00000370826.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypotrichosis 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606869; hg19: chr8-21988118;